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ABSTRACT

  • Oncogenes are altered forms of normal cellular genes called proto-oncogenes. In human cancers, proto-oncogenes are frequently located adjacent to chromosomal breakpoints and are targets for mutation. The products of proto-oncogenes are highly conserved in evolution and serve to regulate the cascade of events that maintains the ordered progression through the cell cycle, cell division, and differentiation. In the cancer cell, this ordered progression is partially lost when one or more of the components of this pathway are altered.

  • The control of normal cell growth and differentiation is mediated by the interaction of growth factors and cytokines with their membrane-bound receptors. This event triggers a cascade of intracellular biochemical signals that eventually results in the activation and repression of various genes. Proto-oncogene products have been shown to function at critical steps in these pathways and include proteins such as extracellular cytokines and growth factors, transmembrane growth factor receptors, cytoplasmic proteins that act to transmit the signal to the nucleus, and nuclear proteins that include transcription factors and proteins involved in the control of DNA replication.

  • Accumulating evidence suggests that the activation of several oncogenes and the inactivation of several growth-suppressor genes are necessary for acquisition of a complete neoplastic phenotype. It has been possible from experimental studies to subdivide oncogenes into several groups. One class of genes rescues cells from senescence and programmed cell death; they act as immortalizing genes that block cell differentiation. A second class of genes reduces growth factor requirements and induces changes in cell shape that result in a continuous proliferative response that is no longer regulated.

  • The use of transgenic mice is providing a powerful experimental approach to investigate the role of oncogenes in cancer. Oncogene expression can be directed to specific tissues, where a role for the oncogene in tumor formation in those tissues can be evaluated. Although transgenic mouse strains carrying a single oncogene generally show an increased incidence of neoplasia, oncogene expression usually precedes tumor formation by many months, and the tumors that result are frequently clonal, implying that other events are necessary. Examination of the secondary events in tumors from oncogene-bearing transgenic mice has confirmed the conclusions derived from in vitro studies and has identified new oncogenes. By crossing two strains of oncogene-bearing mice, the consequence of multiple oncogenes on tumor incidence can be studied in a host capable of mounting a physiological response.

INTRODUCTION

In the past 15 years, the study of oncogenes has considerably advanced our understanding of the molecular mechanisms leading to cancer. The application of techniques from many cancer research disciplines has led to the discovery of both dominantly acting transforming genes and of tumor-suppressor genes. The dominant transforming genes, collectively called oncogenes, are altered forms of normal cellular genes called proto-oncogenes. Proto-oncogenes are highly conserved in evolution, and their products are important regulators of normal cell growth and differentiation from primitive eukaryotes to humans. They are localized throughout the cell ...

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